Persistence of hyperdense middle cerebral artery sign on follow-up CT scan after intravenous thrombolysis is associated with poor outcome.

BACKGROUND: The rates and extent of recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA) remain highly variable. Hyperdense middle cerebral artery sign (HMCAS) on pretreatment unenhanced computerized tomography (CT) of the brain represents the presence of thrombus, often associated with severe neurological deficits and poor clinical outcome at 3 months. However, HMCAS is reliable only in AIS patients managed conservatively. In patients treated with systemic thrombolysis, HMCAS may disappear (representing clot dissolution) or persist (persisting clot) on the follow-up CT scan of the brain. We aimed at evaluating whether disappearance or the persistence of HMCAS on follow-up CT scan of the brain can predict the final outcome at 3 months. METHODS: Data from consecutive AIS patients treated with IV-tPA, in a standardized protocol, from January 2007 to March 2010 were included in the prospective thrombolysis registry at our tertiary care center. For this evaluation, posterior circulation stroke was excluded. HMCAS was assessed on admission as well as follow-up CT by 2 independent stroke neurologists, blinded to the patient data or outcomes. Functional outcomes assessed by the modified Rankin Scale (mRS) at 3 months were dichotomized as good (mRS score 0-1) and poor (mRS score 2-6). The data were analyzed for the early predictors of poor functional outcome with SPSS version 19 for Windows. RESULTS: Of the total of 2,238 patients admitted during the study period, 226 (11%) with anterior circulation AIS treated with intravenous thrombolysis were included. Median age of the patients was 65 years (range 19-92), 63% were males and they had a median National Institutes of Health Stroke Scale (NIHSS) score of 16 points (range 4-32). HMCAS was observed on admission CT scan in 109 (48.2%) patients and persisted on follow-up CT in 52 (47.7%) of them. Overall, 108 (47.8%) patients achieved poor functional outcome at 3 months. Admission NIHSS score (OR per 1-point increase = 1.241; 95% CI = 1.151-1.337, p < 0.0005), lesser change in NIHSS score at 24 h (OR per 1-point reduction = 0.730; 95% CI = 0.666-0.800, p < 0.0005) and persistence of HMCAS on follow-up CT scan (OR = 3.352; 95% CI = 1.991-11.333, p = 0.039) were associated with poor outcome at 3 months. CONCLUSION: Persistence of HMCAS on the follow-up CT scan of the brain in acute ischemic stroke patients treated with IV-tPA can be used as an early predictor of poor functional outcome.

Stroke risk factors and outcomes among various Asian ethnic groups in Singapore.

Data on interethnic differences in the Asian stroke population are limited. We evaluated the relationships among various cardiovascular risk factors, stroke subtypes, and outcomes in a multiethnic Singaporean population comprising consecutive ischemic stroke patients presenting to our tertiary center over a 1-year period. Strokes were classified based on criteria used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Functional independence at hospital discharge was defined as a modified Rankin Scale (mRS) score of 0-2. The ethnic distribution of the study population (n = 481; mean age, 64.1 ± 11.9 years) was 74% Chinese, 17% Malay, and 9% Indian. The prevalence of risk factors was similar in the 3 ethnic groups except for diabetes (Chinese, 39.8%; Malay, 67.5%; Indian, 52.3%; P < .001). Hypertension and hypercholesterolemia were the most common cardiovascular risk factors. Lacunar stroke was the most frequent stroke subtype (47.9%). Large-artery atherosclerotic infarctions were more prevalent in Indians (25.0%), whereas lacunar infarctions occured more frequently in Chinese (51.8%; P < .01). No differences in in-hospital mortality and functional independence at discharge were seen among the 3 ethnic groups. Despite the differences in risk factors and in stroke subtypes classified by location or underlying etiology, short-term outcome measures were similar in the 3 different Asian ethnicities in Singapore.

Oxidative damage in ischemic stroke revealed using multiple biomarkers.

BACKGROUND AND PURPOSE: We investigated changes in oxidative damage after ischemic stroke using multiple biomarkers. METHODS: Serial blood and urine samples of ischemic stroke subjects and age-matched control subjects were assayed for F2-isoprostanes, hydroxyeicosatetraenoic acid products, F4-neuroprostanes, 24-hydroxycholesterol, allantoin, and urate. RESULTS: Sixty-six stroke subjects (mean age, 65 years; median National Institutes of Health Stroke Scale 17) and 132 control subjects were recruited. A bimodal pattern of change was observed in plasma and urinary F2-isoprostanes and plasma 24-hydroxycholesterol. The rise in plasma hydroxyeicosatetraenoic acid products, F4-neuroprostanes, and allantoin was highest 6 to 12 hours after stroke onset, whereas plasma urate was significantly lower than controls on Days 1 to 3. After adjusting for age and baseline National Institutes of Health Stroke Scale, baseline plasma esterified hydroxyeicosatetraenoic acid products (OR, 1.01; 95% CI, 1.01 to 1.02), plasma urate (1.01; 1.00 to 1.01), and plasma free F4-neuroprostanes (2.73; 1.76 to 3.93) were associated with 90-day good functional recovery (modified Rankin Scale ≤1). CONCLUSIONS: Multiple markers of oxidative damage are increased immediately after stroke and remain elevated for several days. Recognition of these temporal changes may help design better antioxidant treatment trials for acute ischemic stroke.

Recanalization therapies in acute ischemic stroke: pharmacological agents, devices, and combinations.

The primary aim of thrombolysis in acute ischemic stroke is recanalization of an occluded intracranial artery. Recanalization is an important predictor of stroke outcome as timely restoration of regional cerebral perfusion helps salvage threatened ischemic tissue. At present, intravenously administered tissue plasminogen activator (IV-TPA) remains the only FDA-approved therapeutic agent for the treatment of ischemic stroke within 3 hours of symptom onset. Recent studies have demonstrated safety as well as efficacy of IV-TPA even in an extended therapeutic window. However, the short therapeutic window, low rates of recanalization, and only modest benefits with IV-TPA have prompted a quest for alternative approaches to restore blood flow in an occluded artery in acute ischemic stroke. Although intra-arterial delivery of the thrombolytic agent seems effective, various logistic constraints limit its routine use and as yet no lytic agent have not received full regulatory approval for intra-arterial therapy. Mechanical devices and approaches can achieve higher rates of recanalization but their safety and efficacy still need to be established in larger clinical trials. The field of acute revascularization is rapidly evolving, and various combinations of pharmacologic agents, mechanical devices, and novel microbubble/ultrasound technologies are being tested in multiple clinical trials.

Feasibility and safety of intravenous thrombolysis in multiethnic Asian stroke patients in Singapore.

Treatment rates with intravenously administered tissue plasminogen activator (IV-tPA) in acute ischemic stroke (IS) remain low in Asian populations. Various logistic obstacles and higher anticipated bleeding risk in Asians are major concerns. We report on the feasibility and safety of IV-tPA therapy at our tertiary care center. Consecutive acute IS patients eligible for thrombolysis were treated with low-dose (maximum 50 mg) IV-tPA between January 2000 and September 2006 and with standard-dose (maximum 90 mg) IV-tPA between October 2006 and May 2008. The efficacy of IV-tPA was assessed by the modified Rankin Scale (mRS) score at 3 months and by absolute changes in the National Institute of Health Stroke Scale (NIHSS) score at hospital discharge and 3 months. The safety of IV-tPA was assessed by the rate of symptomatic intracranial hemorrhage (SICH). A total of 130 patients were included (mean age, 60±13 years; 60% males; median NIHSS score, 14). A total of 48 patients received low-dose IV-tPA, and 82 patients received standard-dose IV-tPA. The median onset to treatment time was 160 minutes. Some 59% of the patients achieved functional independence (mRS score 0-1) at 3 months with standard-dose tPA, compared with 35% in the low-dose group (P=.011). SICH occurred more frequently with the low dose (14.5%) than with the standard dose (1.2%; P=.004). In a multivariate logistic regression model, lower admission NIHSS score (odds ratio [OR]=0.78 per 1-point increase; 95% confidence interval [CI]=0.70-0.88), lower pretreatment blood glucose level (OR=0.76 per 1 mmol/L increase; 95% CI=0.60-0.95), shorter time from symptom onset to IV-tPA bolus (OR=0.97 per 1-minute increase; 95% CI=0.94-1.0), and standard-dose IV-tPA (OR=12.49; 95% CI=2.9-53.89) were associated with a higher likelihood for functional independence at 3 months. Our data indicate that standard-dose IV-tPA (0.9 mg/kg) was feasible and safe for treating acute IS in our multiethnic Asian population in Singapore.

Reversed flow in the basilar artery in acute vertebrobasilar ischemia.

Acute vertebrobasilar ischemia is a potentially sinister pathology with high mortality and poor functional outcome in survivors. We report the findings of multi-modal assessment (MRI and cerebrovascular ultrasonography) of cerebral hemodynamics in a patient who suffered from acute brainstem infarction with National Institute of Health Stroke Scale (NIHSS) score of 16 points. Our patient demonstrated reversal of blood flow in the basilar artery on the second day of his stroke and this was associated with significant and rapid clinical recovery over the following 2 days (NIHSS score dropped to 4 points). He had recovered completely when seen in the outpatient clinic 3 months later.

Venous thromboembolism at the National Healthcare Group, Singapore.

INTRODUCTION: Venous thromboembolism (VTE), including its most serious clinical subtype, pulmonary embolism (PE), is a potentially preventable disease. While current assessment tools do not include ethnicity as a risk factor, studies suggest that Asians have lower risk of VTE compared to Caucasians. This study aims to describe 2006 in-hospital and projected population based incidence rates of VTE and PE in Singapore. MATERIALS AND METHODS: Data on 2006 admissions at 3 major NHG hospitals, cases of VTE and their demographics were obtained from the ODS, a large administrative database of the National Healthcare Group (NHG). Demographic characteristics of the 2006 Singapore resident population were obtained from the 2006 Singapore Statistics website. RESULTS: In 2006, there were 860 cases of VTE out of 98,121 admissions in these 3 hospitals. Overall and secondary VTE age adjusted in-hospital burden was 73 and 54 per 10,000 patients, respectively. Caucasians and Eurasians had VTE rates in excess of 100 per 10,000 while Chinese, Malays and Indians each had rates below 100 per 10,000. Assuming that 42.5% of the 2006 Singapore population was served by NHG, the estimated population-based incidence of VTE and PE is 57 and 15 per 100,000, respectively. CONCLUSIONS: As patterns across ethnic groups point to lower VTE rates among Asians compared to Caucasians and Eurasians, analytic studies should be considered to test this hypothesis. There may be a need to develop locally applicable risk assessment tools which can be used to support local guidelines for VTE prophylaxis, thus leading to more acceptable and cost-effective care.

Can demographic and admission laboratory variables be useful to identify long-stay patients with acute ischemic stroke? A hospital-based cohort study in Singapore.

The demographic and laboratory predictors of long-stay patients with ischemic stroke were sought in this retrospective hospital-based study. In the univariate and multivariate analysis, advanced age, male gender, leukocytosis, elevated creatinine, low-serum albumin, elevated alkaline transaminases, and lactate dehydrogenase were identified as independent predictors of "long" stayers. At an optimal probability cut-offs, the receiver operating curve incorporating these variables was 0.70, sensitivity 68%, specificity 80%, positive-predictive value 39% and negative-predictive value 95%. Application of this information may assist physicians to triage patients at risk of severe stroke for early therapy and care.

Ultrasound assisted thrombolysis in acute ischaemic stroke: preliminary experience in Singapore.

BACKGROUND AND AIM: Intravenously-administered tissue plasminogen activator (IV-TPA) induces thrombolysis and remains the only FDA-approved therapy for acute ischaemic stroke. IV-TPA thrombolysis has been approved recently in Singapore for acute stroke. Continuous exposure of clot to 2-MHz pulsed-wave transcranial Doppler (TCD) ultrasound during IV-TPA infusion is known to augment thrombolysis. We aimed to determine the feasibility, safety and efficacy of ultrasound-assisted thrombolysis in acute ischaemic stroke in Singapore. SUBJECTS AND METHODS: Consecutive patients with acute ischaemic stroke due to intracranial arterial-occlusions were treated with standard IV-tPA and continuously monitored with 2-MHz TCD according to the CLOTBUST-trial protocol. Arterial recanalisation was determined with Thrombolysis in Brain Ischemia (TIBI) flow-grading system. Safety and efficacy of ultrasoundassisted thrombolysis were assessed by rates of symptomatic intracranial haemorrhage (sICH) and functional recovery at 1 month, respectively. RESULTS: Five consecutive patients (mean age 58 years, 3 men and 3 of Chinese ethnicity) were included. Mean time elapsed between symptom onset and presentation to emergency room was 98 minutes (range, 50 to 135 minutes) while the mean time interval between symptom onset to IV-TPA bolus was 144 minutes (range, 125 to 180 minutes). Partial or complete recanalisation with reduction in the stroke severity was noted in 4 out of the 5 patients during IV-TPA infusion (mean change in NIHSS = 4 points; range 2 to 8 points). None of our patients developed sICH while 4 patients demonstrated good functional outcome at 1 month. CONCLUSIONS: Our preliminary study demonstrates the feasibility, safety and efficacy of ultrasound-assisted thrombolysis in acute ischaemic stroke in Singapore. Continuous TCD-monitoring during IV-TPA infusion provides real-time information, enhances thrombolysis and improves functional outcomes in acute ischaemic stroke.

Novel chloride channel mutations leading to mild myotonia among Chinese.

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.

Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation.

The S218L CACNA1A mutation has been previously described in two families with familial hemiplegic migraine. We present three siblings with the mutation with the novel association of childhood seizures, and highlight the dynamic changes seen on electroencephalography during hemiplegic migraine attacks. Depressed activity contralateral to the hemiparesis was seen on electroencephalography during acute hemiplegic migraine attacks, which may be due to changes to calcium channels caused by the S218L mutation. Both parents were asymptomatic and did not carry the S218L mutation in their blood. This suggests the presence of mosaicism in the transmitting parent.

Computer-based testing of the modified essay question: the Singapore experience.

BACKGROUND: The modified essay question (MEQ), featuring an evolving case scenario, tests a candidate's problem-solving and reasoning ability, rather than mere factual recall. Although it is traditionally conducted as a pen-and-paper examination, our university has run the MEQ using computer-based testing (CBT) since 2003. AIMS: We describe our experience with running the MEQ examination using the IVLE, or integrated virtual learning environment (https://ivle.nus.edu.sg), provide a blueprint for universities intending to conduct computer-based testing of the MEQ, and detail how our MEQ examination has evolved since its inception. METHODS: An MEQ committee, comprising specialists in key disciplines from the departments of Medicine and Paediatrics, was formed. We utilized the IVLE, developed for our university in 1998, as the online platform on which we ran the MEQ. We calculated the number of man-hours (academic and support staff) required to run the MEQ examination, using either a computer-based or pen-and-paper format. RESULTS: With the support of our university's information technology (IT) specialists, we have successfully run the MEQ examination online, twice a year, since 2003. Initially, we conducted the examination with short-answer questions only, but have since expanded the MEQ examination to include multiple-choice and extended matching questions. A total of 1268 man-hours was spent in preparing for, and running, the MEQ examination using CBT, compared to 236.5 man-hours to run it using a pen-and-paper format. Despite being more labour-intensive, our students and staff prefer CBT to the pen-and-paper format. CONCLUSIONS: The MEQ can be conducted using a computer-based testing scenario, which offers several advantages over a pen-and-paper format. We hope to increase the number of questions and incorporate audio and video files, featuring clinical vignettes, to the MEQ examination in the near future.

POEMS syndrome--a case for more aggressive treatment.

INTRODUCTION: Patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal or M-protein and skin changes) syndrome exhibit a wide range of clinical manifestations and are often seen by a variety of specialists prior to diagnosis. CLINICAL PICTURE: We describe a case of POEMS syndrome that first presented with significant neuropathy but progressed to develop further manifestations of the condition, including marked gastrointestinal symptoms. TREATMENT: The patient was commenced on localised radiotherapy and chemotherapy in addition to immunomodulatory therapy for the neuropathy. CONCLUSION: We highlight several learning points that may benefit physicians from varied specialties. This case is also unique for its marked gastrointestinal manifestation. To our knowledge, this is the second reported case in the literature with this feature.

Is there a place for placebo in management of psychogenic movement disorders?

INTRODUCTION: The management of psychogenic movement disorders is fraught with difficulties. Empathy and a non-judgmental manner are essential in dealing with patients, and a neurobiological explanation of the symptoms may help to foster trust, acceptance, understanding and recovery. CLINICAL PICTURE: We report a 17-year-old Chinese girl with psychogenic blepharospasm. Her parents refused psychotherapy and pharmacotherapy. TREATMENT AND OUTCOME: Placebo therapy (with parental consent) was prescribed with favourable results. CONCLUSION: We examine the ethical considerations for and against placebo therapy, and explore the role of placebo therapy in the management of psychogenic movement disorders.

Computer-based versus pen-and-paper testing: students' perception.

BACKGROUND: Computer-based testing (CBT) has become increasingly popular as a testing modality in under- and postgraduate medical education. Since 2004, our medical school has utilised CBT to conduct 2 papers for the third- and final-year assessments - Paper 3, with 30 multiple choice questions featuring clinical vignettes, and the modified essay question (MEQ) paper. AIMS: To obtain feedback from final-year students on their preferred mode of testing for Paper 3 and MEQ components of the Medicine track examination, and the reasons underlying their preferences. METHODS: An online survey was carried out on 213 final-year undergraduates, in which they were asked to provide feedback on Paper 3 and MEQ papers. Students were asked if they thought that the CBT format was preferable to the pen-and-paper (PNP) format for Paper 3 and the MEQ, and why. RESULTS: One hundred and fourteen out of 213 (53.5%) students completed the online survey. For Paper 3, 91 (79.8%) felt that CBT was preferable to PNP, 11 (9.6%) preferred the PNP format and 12 (10.5%) were unsure. For the MEQ, 62 (54.4%) preferred CBT over PNP, 30 (26.3%) preferred the PNP format and 22 (19.3%) were unsure. Reasons given to explain preference for CBT over PNP for Paper 3 included independence from seating position, better image quality (as images were shown on personal computer screens instead of projected onto a common screen) and the fact that CBT allowed them to proceed at their own pace. For the MEQ, better image quality, neater answer scripts and better indication of answer length in CBT format were cited as reasons for their preference. CONCLUSIONS: Our survey indicated that whereas the majority of students preferred CBT over PNP for Paper 3, a smaller margin had the same preference for the MEQ.